ERC FUNDED PROJECTS

Project1D-electrons coupled to dissipation: a novel approach for understanding and engineering superconducting materials and devices

Researcher (PI)Adrian KANTIAN

Host Institution (HI)UPPSALA UNIVERSITET

Call DetailsStarting Grant (StG), PE3, ERC-2017-STG

SummaryCorrelated electrons are at the forefront of condensed matter theory. Interacting quasi-1D electrons have seen vast progress in analytical and numerical theory, and thus in fundamental understanding and quantitative prediction. Yet, in the 1D limit fluctuations preclude important technological use, particularly of superconductors. In contrast, high-Tc superconductors in 2D/3D are not precluded by fluctuations, but lack a fundamental theory, making prediction and engineering of their properties, a major goal in physics, very difficult. This project aims to combine the advantages of both areas by making major progress in the theory of quasi-1D electrons coupled to an electron bath, in part building on recent breakthroughs (with the PIs extensive involvement) in simulating 1D and 2D electrons with parallelized density matrix renormalization group (pDMRG) numerics. Such theory will fundamentally advance the study of open electron systems, and show how to use 1D materials as elements of new superconducting (SC) devices and materials: 1) It will enable a new state of matter, 1D electrons with true SC order. Fluctuations from the electronic liquid, such as graphene, could also enable nanoscale wires to appear SC at high temperatures. 2) A new approach for the deliberate engineering of a high-Tc superconductor. In 1D, how electrons pair by repulsive interactions is understood and can be predicted. Stabilization by reservoir - formed by a parallel array of many such 1D systems - offers a superconductor for which all factors setting Tc are known and can be optimized. 3) Many existing superconductors with repulsive electron pairing, all presently not understood, can be cast as 1D electrons coupled to a bath. Developing chain-DMFT theory based on pDMRG will allow these materials SC properties to be simulated and understood for the first time. 4) The insights gained will be translated to 2D superconductors to study how they could be enhanced by contact with electronic liquids.

Correlated electrons are at the forefront of condensed matter theory. Interacting quasi-1D electrons have seen vast progress in analytical and numerical theory, and thus in fundamental understanding and quantitative prediction. Yet, in the 1D limit fluctuations preclude important technological use, particularly of superconductors. In contrast, high-Tc superconductors in 2D/3D are not precluded by fluctuations, but lack a fundamental theory, making prediction and engineering of their properties, a major goal in physics, very difficult. This project aims to combine the advantages of both areas by making major progress in the theory of quasi-1D electrons coupled to an electron bath, in part building on recent breakthroughs (with the PIs extensive involvement) in simulating 1D and 2D electrons with parallelized density matrix renormalization group (pDMRG) numerics. Such theory will fundamentally advance the study of open electron systems, and show how to use 1D materials as elements of new superconducting (SC) devices and materials: 1) It will enable a new state of matter, 1D electrons with true SC order. Fluctuations from the electronic liquid, such as graphene, could also enable nanoscale wires to appear SC at high temperatures. 2) A new approach for the deliberate engineering of a high-Tc superconductor. In 1D, how electrons pair by repulsive interactions is understood and can be predicted. Stabilization by reservoir - formed by a parallel array of many such 1D systems - offers a superconductor for which all factors setting Tc are known and can be optimized. 3) Many existing superconductors with repulsive electron pairing, all presently not understood, can be cast as 1D electrons coupled to a bath. Developing chain-DMFT theory based on pDMRG will allow these materials SC properties to be simulated and understood for the first time. 4) The insights gained will be translated to 2D superconductors to study how they could be enhanced by contact with electronic liquids.

Max ERC Funding

1 491 013 €

Duration

Start date: 2018-10-01, End date: 2023-09-30

Project acronym3DPROTEINPUZZLES

ProjectShape-directed protein assembly design

Researcher (PI)Lars Ingemar ANDRÉ

Host Institution (HI)LUNDS UNIVERSITET

Call DetailsConsolidator Grant (CoG), LS9, ERC-2017-COG

SummaryLarge protein complexes carry out some of the most complex functions in biology. Such structures are often assembled spontaneously from individual components through the process of self-assembly. If self-assembled protein complexes could be engineered from first principle it would enable a wide range of applications in biomedicine, nanotechnology and materials science. Recently, approaches to rationally design proteins to self-assembly into predefined structures have emerged. The highlight of this work is the design of protein cages that may be engineered into protein containers. However, current approaches for self-assembly design does not result in the assemblies with the required structural complexity to encode many of the sophisticated functions found in nature. To move forward, we have to learn how to engineer protein subunits with more than one designed interface that can assemble into tightly interacting complexes. In this proposal we propose a new protein design paradigm, shape directed protein design, in order to address shortcomings of the current methodology. The proposed method combines geometric shape matching and computational protein design. Using this approach we will de novo design assemblies with a wide variety of structural states, including protein complexes with cyclic and dihedral symmetry as well as icosahedral protein capsids built from novel protein building blocks. To enable these two design challenges we also develop a high-throughput assay to measure assembly stability in vivo that builds on a three-color fluorescent assay. This method will not only facilitate the screening of orders of magnitude more design constructs, but also enable the application of directed evolution to experimentally improve stable and assembly properties of designed containers as well as other designed assemblies.

Large protein complexes carry out some of the most complex functions in biology. Such structures are often assembled spontaneously from individual components through the process of self-assembly. If self-assembled protein complexes could be engineered from first principle it would enable a wide range of applications in biomedicine, nanotechnology and materials science. Recently, approaches to rationally design proteins to self-assembly into predefined structures have emerged. The highlight of this work is the design of protein cages that may be engineered into protein containers. However, current approaches for self-assembly design does not result in the assemblies with the required structural complexity to encode many of the sophisticated functions found in nature. To move forward, we have to learn how to engineer protein subunits with more than one designed interface that can assemble into tightly interacting complexes. In this proposal we propose a new protein design paradigm, shape directed protein design, in order to address shortcomings of the current methodology. The proposed method combines geometric shape matching and computational protein design. Using this approach we will de novo design assemblies with a wide variety of structural states, including protein complexes with cyclic and dihedral symmetry as well as icosahedral protein capsids built from novel protein building blocks. To enable these two design challenges we also develop a high-throughput assay to measure assembly stability in vivo that builds on a three-color fluorescent assay. This method will not only facilitate the screening of orders of magnitude more design constructs, but also enable the application of directed evolution to experimentally improve stable and assembly properties of designed containers as well as other designed assemblies.

Max ERC Funding

2 325 292 €

Duration

Start date: 2018-06-01, End date: 2023-05-31

Project acronym3DWATERWAVES

ProjectMathematical aspects of three-dimensional water waves with vorticity

Researcher (PI)Erik Torsten Wahlén

Host Institution (HI)LUNDS UNIVERSITET

Call DetailsStarting Grant (StG), PE1, ERC-2015-STG

SummaryThe goal of this project is to develop a mathematical theory for steady three-dimensional water waves with vorticity. The mathematical model consists of the incompressible Euler equations with a free surface, and vorticity is important for modelling the interaction of surface waves with non-uniform currents. In the two-dimensional case, there has been a lot of progress on water waves with vorticity in the last decade. This progress has mainly been based on the stream function formulation, in which the problem is reformulated as a nonlinear elliptic free boundary problem. An analogue of this formulation is not available in three dimensions, and the theory has therefore so far been restricted to irrotational flow. In this project we seek to go beyond this restriction using two different approaches. In the first approach we will adapt methods which have been used to construct three-dimensional ideal flows with vorticity in domains with a fixed boundary to the free boundary context (for example Beltrami flows). In the second approach we will develop methods which are new even in the case of a fixed boundary, by performing a detailed study of the structure of the equations close to a given shear flow using ideas from infinite-dimensional bifurcation theory. This involves handling infinitely many resonances.

The goal of this project is to develop a mathematical theory for steady three-dimensional water waves with vorticity. The mathematical model consists of the incompressible Euler equations with a free surface, and vorticity is important for modelling the interaction of surface waves with non-uniform currents. In the two-dimensional case, there has been a lot of progress on water waves with vorticity in the last decade. This progress has mainly been based on the stream function formulation, in which the problem is reformulated as a nonlinear elliptic free boundary problem. An analogue of this formulation is not available in three dimensions, and the theory has therefore so far been restricted to irrotational flow. In this project we seek to go beyond this restriction using two different approaches. In the first approach we will adapt methods which have been used to construct three-dimensional ideal flows with vorticity in domains with a fixed boundary to the free boundary context (for example Beltrami flows). In the second approach we will develop methods which are new even in the case of a fixed boundary, by performing a detailed study of the structure of the equations close to a given shear flow using ideas from infinite-dimensional bifurcation theory. This involves handling infinitely many resonances.

SummaryDeveloping new therapeutic strategies for heart regeneration is a major goal for cardiac biology and medicine. While cardiomyocytes can be generated from human pluripotent stem (hPSC) cells in vitro, it has proven difficult to use these cells to generate a large scale, mature human heart ventricular muscle graft on the injured heart in vivo. The central objective of this proposal is to optimize the generation of a large-scale pure, fully functional human ventricular muscle patch in vivo through the self-assembly of purified human ventricular progenitors and the localized expression of defined paracrine factors that drive their expansion, differentiation, vascularization, matrix formation, and maturation. Recently, we have found that purified hPSC-derived ventricular progenitors (HVPs) can self-assemble in vivo on the epicardial surface into a 3D vascularized, and functional ventricular patch with its own extracellular matrix via a cell autonomous pathway. A two-step protocol and FACS purification of HVP receptors can generate billions of pure HVPs- The current proposal will lead to the identification of defined paracrine pathways to enhance the survival, grafting/implantation, expansion, differentiation, matrix formation, vascularization and maturation of the graft in vivo. We will captalize on our unique HVP system and our novel modRNA technology to deliver therapeutic strategies by using the in vivo human ventricular muscle to model in vivo arrhythmogenic cardiomyopathy, and optimize the ability of the graft to compensate for the massive loss of functional muscle during ischemic cardiomyopathy and post-myocardial infarction. The studies will lead to new in vivo chimeric models of human cardiac disease and an experimental paradigm to optimize organ-on-organ cardiac tissue engineers of an in vivo, functional mature ventricular patch for cardiomyopathy

Developing new therapeutic strategies for heart regeneration is a major goal for cardiac biology and medicine. While cardiomyocytes can be generated from human pluripotent stem (hPSC) cells in vitro, it has proven difficult to use these cells to generate a large scale, mature human heart ventricular muscle graft on the injured heart in vivo. The central objective of this proposal is to optimize the generation of a large-scale pure, fully functional human ventricular muscle patch in vivo through the self-assembly of purified human ventricular progenitors and the localized expression of defined paracrine factors that drive their expansion, differentiation, vascularization, matrix formation, and maturation. Recently, we have found that purified hPSC-derived ventricular progenitors (HVPs) can self-assemble in vivo on the epicardial surface into a 3D vascularized, and functional ventricular patch with its own extracellular matrix via a cell autonomous pathway. A two-step protocol and FACS purification of HVP receptors can generate billions of pure HVPs- The current proposal will lead to the identification of defined paracrine pathways to enhance the survival, grafting/implantation, expansion, differentiation, matrix formation, vascularization and maturation of the graft in vivo. We will captalize on our unique HVP system and our novel modRNA technology to deliver therapeutic strategies by using the in vivo human ventricular muscle to model in vivo arrhythmogenic cardiomyopathy, and optimize the ability of the graft to compensate for the massive loss of functional muscle during ischemic cardiomyopathy and post-myocardial infarction. The studies will lead to new in vivo chimeric models of human cardiac disease and an experimental paradigm to optimize organ-on-organ cardiac tissue engineers of an in vivo, functional mature ventricular patch for cardiomyopathy

SummaryThe ERC StG project UNICON (Project ID 202984) was completed in July 2013. The goal of UNICON was to develop new adaptive finite element methods for computer simulation of fluid-structure interaction, in particular for problems involving turbulent flow. Simulation of turbulent flow is an outstanding computational challenge, where the UNICON project made significant progress beyond the state of the art. The scientific results of the UNICON project include a new theoretical and methodological framework, and a computer implementation of the methods as open source software, published as part of the FEniCS project, co-founded by the PI (Hoffman) in 2003. FEniCS is today a world leading open source software for computer simulation based on differential equations, with an estimated 50 000 downloads per year, and the PI today leads the PRACE Tier-0 project FEniCS-HPC, in which algorithms and software are developed for the most powerful supercomputers in Europe. Compared to competing simulation software, free as well as commercial, UNICON computational technology has proven to exhibit unique features with respect to accuracy and efficiency.
The idea of this ERC PoC project is to commercialize the UNICON simulation technology. In particular, ADAPTIVE targets civil (non-military) industry, with a focus on subsonic fluid dynamics. The strategy is to deliver services and products tailored to each customer, from deliverance of a simulation result, to education and support for integration of the simulation tools in the workflow of a customer.

The ERC StG project UNICON (Project ID 202984) was completed in July 2013. The goal of UNICON was to develop new adaptive finite element methods for computer simulation of fluid-structure interaction, in particular for problems involving turbulent flow. Simulation of turbulent flow is an outstanding computational challenge, where the UNICON project made significant progress beyond the state of the art. The scientific results of the UNICON project include a new theoretical and methodological framework, and a computer implementation of the methods as open source software, published as part of the FEniCS project, co-founded by the PI (Hoffman) in 2003. FEniCS is today a world leading open source software for computer simulation based on differential equations, with an estimated 50 000 downloads per year, and the PI today leads the PRACE Tier-0 project FEniCS-HPC, in which algorithms and software are developed for the most powerful supercomputers in Europe. Compared to competing simulation software, free as well as commercial, UNICON computational technology has proven to exhibit unique features with respect to accuracy and efficiency.
The idea of this ERC PoC project is to commercialize the UNICON simulation technology. In particular, ADAPTIVE targets civil (non-military) industry, with a focus on subsonic fluid dynamics. The strategy is to deliver services and products tailored to each customer, from deliverance of a simulation result, to education and support for integration of the simulation tools in the workflow of a customer.

SummaryOur affective and motivational state is important for our decisions, actions and quality of life. Many pathological conditions affect this state. For example, addictive drugs are hyperactivating the reward system and trigger a strong motivation for continued drug intake, whereas many somatic and psychiatric diseases lead to an aversive state, characterized by loss of motivation. I will study specific neural circuits and mechanisms underlying reward and aversion, and how pathological signaling in these systems can trigger relapse in drug addiction.
Given the important role of the dopaminergic neurons in the midbrain for many aspects of reward signaling, I will study how synaptic plasticity in these cells, and in their target neurons in the striatum, contribute to relapse in drug seeking. I will also study the circuits underlying aversion. Little is known about these circuits, but my hypothesis is that an important component of aversion is signaled by a specific neuronal population in the brainstem parabrachial nucleus, projecting to the central amygdala. We will test this hypothesis and also determine how this aversion circuit contributes to the persistence of addiction and to relapse.
To dissect this complicated system, I am developing new genetic methods for manipulating and visualizing specific functional circuits in the mouse brain. My unique combination of state-of-the-art competence in transgenics and cutting edge knowledge in the anatomy and functional organization of the circuits behind reward and aversion should allow me to decode these systems, linking discrete circuits to behavior.
Collectively, the results will indicate how signals encoding aversion and reward are integrated to control addictive behavior and they may identify novel avenues for treatment of drug addiction as well as aversion-related symptoms affecting patients with chronic inflammatory conditions and cancer.

Our affective and motivational state is important for our decisions, actions and quality of life. Many pathological conditions affect this state. For example, addictive drugs are hyperactivating the reward system and trigger a strong motivation for continued drug intake, whereas many somatic and psychiatric diseases lead to an aversive state, characterized by loss of motivation. I will study specific neural circuits and mechanisms underlying reward and aversion, and how pathological signaling in these systems can trigger relapse in drug addiction.
Given the important role of the dopaminergic neurons in the midbrain for many aspects of reward signaling, I will study how synaptic plasticity in these cells, and in their target neurons in the striatum, contribute to relapse in drug seeking. I will also study the circuits underlying aversion. Little is known about these circuits, but my hypothesis is that an important component of aversion is signaled by a specific neuronal population in the brainstem parabrachial nucleus, projecting to the central amygdala. We will test this hypothesis and also determine how this aversion circuit contributes to the persistence of addiction and to relapse.
To dissect this complicated system, I am developing new genetic methods for manipulating and visualizing specific functional circuits in the mouse brain. My unique combination of state-of-the-art competence in transgenics and cutting edge knowledge in the anatomy and functional organization of the circuits behind reward and aversion should allow me to decode these systems, linking discrete circuits to behavior.
Collectively, the results will indicate how signals encoding aversion and reward are integrated to control addictive behavior and they may identify novel avenues for treatment of drug addiction as well as aversion-related symptoms affecting patients with chronic inflammatory conditions and cancer.

Max ERC Funding

1 500 000 €

Duration

Start date: 2010-10-01, End date: 2015-09-30

Project acronymAfricanNeo

ProjectThe African Neolithic: A genetic perspective

Researcher (PI)Carina SCHLEBUSCH

Host Institution (HI)UPPSALA UNIVERSITET

Call DetailsStarting Grant (StG), SH6, ERC-2017-STG

SummaryThe spread of farming practices in various parts of the world had a marked influence on how humans live today and how we are distributed around the globe. Around 10,000 years ago, warmer conditions lead to population increases, coinciding with the invention of farming in several places around the world. Archaeological evidence attest to the spread of these practices to neighboring regions. In many cases this lead to whole continents being converted from hunter-gatherer to farming societies. It is however difficult to see from archaeological records if only the farming culture spread to other places or whether the farming people themselves migrated. Investigating patterns of genetic variation for farming populations and for remaining hunter-gatherer groups can help to resolve questions on population movements co-occurring with the spread of farming practices. It can further shed light on the routes of migration and dates when migrants arrived.
The spread of farming to Europe has been thoroughly investigated in the fields of archaeology, linguistics and genetics, while on other continents these events have been less investigated. In Africa, mainly linguistic and archaeological studies have attempted to elucidate the spread of farming and herding practices. I propose to investigate the movement of farmer and pastoral groups in Africa, by typing densely spaced genome-wide variant positions in a large number of African populations. The data will be used to infer how farming and pastoralism was introduced to various regions, where the incoming people originated from and when these (potential) population movements occurred. Through this study, the Holocene history of Africa will be revealed and placed into a global context of migration, mobility and cultural transitions. Additionally the study will give due credence to one of the largest Neolithic expansion events, the Bantu-expansion, which caused a pronounced change in the demographic landscape of the African continent.

The spread of farming practices in various parts of the world had a marked influence on how humans live today and how we are distributed around the globe. Around 10,000 years ago, warmer conditions lead to population increases, coinciding with the invention of farming in several places around the world. Archaeological evidence attest to the spread of these practices to neighboring regions. In many cases this lead to whole continents being converted from hunter-gatherer to farming societies. It is however difficult to see from archaeological records if only the farming culture spread to other places or whether the farming people themselves migrated. Investigating patterns of genetic variation for farming populations and for remaining hunter-gatherer groups can help to resolve questions on population movements co-occurring with the spread of farming practices. It can further shed light on the routes of migration and dates when migrants arrived.
The spread of farming to Europe has been thoroughly investigated in the fields of archaeology, linguistics and genetics, while on other continents these events have been less investigated. In Africa, mainly linguistic and archaeological studies have attempted to elucidate the spread of farming and herding practices. I propose to investigate the movement of farmer and pastoral groups in Africa, by typing densely spaced genome-wide variant positions in a large number of African populations. The data will be used to infer how farming and pastoralism was introduced to various regions, where the incoming people originated from and when these (potential) population movements occurred. Through this study, the Holocene history of Africa will be revealed and placed into a global context of migration, mobility and cultural transitions. Additionally the study will give due credence to one of the largest Neolithic expansion events, the Bantu-expansion, which caused a pronounced change in the demographic landscape of the African continent.

Max ERC Funding

1 500 000 €

Duration

Start date: 2017-11-01, End date: 2022-10-31

Project acronymAFRODITE

ProjectAdvanced Fluid Research On Drag reduction In Turbulence Experiments

Researcher (PI)Jens Henrik Mikael Fransson

Host Institution (HI)KUNGLIGA TEKNISKA HOEGSKOLAN

Call DetailsStarting Grant (StG), PE8, ERC-2010-StG_20091028

SummaryA hot topic in today's debate on global warming is drag reduction in aeronautics. The most beneficial concept for drag reduction is to maintain the major portion of the airfoil laminar. Estimations show that the potential drag reduction can be as much as 15%, which would give a significant reduction of NOx and CO emissions in the atmosphere considering that the number of aircraft take offs, only in the EU, is over 19 million per year. An important element for successful flow control, which can lead to a reduced aerodynamic drag, is enhanced physical understanding of the transition to turbulence process.
In previous wind tunnel measurements we have shown that roughness elements can be used to sensibly delay transition to turbulence. The result is revolutionary, since the common belief has been that surface roughness causes earlier transition and in turn increases the drag, and is a proof of concept of the passive control method per se. The beauty with a passive control technique is that no external energy has to be added to the flow system in order to perform the control, instead one uses the existing energy in the flow.
In this project proposal, AFRODITE, we will take this passive control method to the next level by making it twofold, more persistent and more robust. Transition prevention is the goal rather than transition delay and the method will be extended to simultaneously control separation, which is another unwanted flow phenomenon especially during airplane take offs. AFRODITE will be a catalyst for innovative research, which will lead to a cleaner sky.

A hot topic in today's debate on global warming is drag reduction in aeronautics. The most beneficial concept for drag reduction is to maintain the major portion of the airfoil laminar. Estimations show that the potential drag reduction can be as much as 15%, which would give a significant reduction of NOx and CO emissions in the atmosphere considering that the number of aircraft take offs, only in the EU, is over 19 million per year. An important element for successful flow control, which can lead to a reduced aerodynamic drag, is enhanced physical understanding of the transition to turbulence process.
In previous wind tunnel measurements we have shown that roughness elements can be used to sensibly delay transition to turbulence. The result is revolutionary, since the common belief has been that surface roughness causes earlier transition and in turn increases the drag, and is a proof of concept of the passive control method per se. The beauty with a passive control technique is that no external energy has to be added to the flow system in order to perform the control, instead one uses the existing energy in the flow.
In this project proposal, AFRODITE, we will take this passive control method to the next level by making it twofold, more persistent and more robust. Transition prevention is the goal rather than transition delay and the method will be extended to simultaneously control separation, which is another unwanted flow phenomenon especially during airplane take offs. AFRODITE will be a catalyst for innovative research, which will lead to a cleaner sky.

SummarySex differences in life span and aging are ubiquitous across the animal kingdom and represent a
long-standing challenge in evolutionary biology. In most species, including humans, sexes differ not
only in how long they live and when they start to senesce, but also in how they react to
environmental interventions aimed at prolonging their life span or decelerating the onset of aging.
Therefore, sex differences in life span and aging have important implications beyond the questions
posed by fundamental science. Both evolutionary reasons and medical implications of sex
differences in demographic, reproductive and physiological senescence are and will be crucial
targets of present and future research in the biology of aging. Here I propose a two-step approach
that can provide a significant breakthrough in our understanding of the biological basis of sex
differences in aging. First, I propose to resolve the age-old conundrum regarding the role of sexspecific
mortality rate in sex differences in aging by developing a series of targeted experimental
evolution studies in a novel model organism – the nematode, Caenorhabditis remanei. Second, I
address the role of intra-locus sexual conflict in the evolution of aging by combining novel
methodology from nutritional ecology – the Geometric Framework – with artificial selection
approach using the cricket Teleogryllus commodus and the fruitfly Drosophila melanogaster. I will
directly test the hypothesis that intra-locus sexual conflict mediates aging by restricting the
adaptive evolution of diet choice. By combining techniques from evolutionary biology and
nutritional ecology, this proposal will raise EU’s profile in integrative research, and contribute to
the training of young scientists in this rapidly developing field.

Sex differences in life span and aging are ubiquitous across the animal kingdom and represent a
long-standing challenge in evolutionary biology. In most species, including humans, sexes differ not
only in how long they live and when they start to senesce, but also in how they react to
environmental interventions aimed at prolonging their life span or decelerating the onset of aging.
Therefore, sex differences in life span and aging have important implications beyond the questions
posed by fundamental science. Both evolutionary reasons and medical implications of sex
differences in demographic, reproductive and physiological senescence are and will be crucial
targets of present and future research in the biology of aging. Here I propose a two-step approach
that can provide a significant breakthrough in our understanding of the biological basis of sex
differences in aging. First, I propose to resolve the age-old conundrum regarding the role of sexspecific
mortality rate in sex differences in aging by developing a series of targeted experimental
evolution studies in a novel model organism – the nematode, Caenorhabditis remanei. Second, I
address the role of intra-locus sexual conflict in the evolution of aging by combining novel
methodology from nutritional ecology – the Geometric Framework – with artificial selection
approach using the cricket Teleogryllus commodus and the fruitfly Drosophila melanogaster. I will
directly test the hypothesis that intra-locus sexual conflict mediates aging by restricting the
adaptive evolution of diet choice. By combining techniques from evolutionary biology and
nutritional ecology, this proposal will raise EU’s profile in integrative research, and contribute to
the training of young scientists in this rapidly developing field.

Max ERC Funding

1 391 904 €

Duration

Start date: 2010-12-01, End date: 2016-05-31

Project acronymALK7

ProjectMetabolic control by the TGF-² superfamily receptor ALK7: A novel regulator of insulin secretion, fat accumulation and energy balance

Researcher (PI)Carlos Ibanez

Host Institution (HI)KAROLINSKA INSTITUTET

Call DetailsAdvanced Grant (AdG), LS4, ERC-2008-AdG

SummaryThe aim of this proposal is to understand a novel regulatory signaling network controlling insulin secretion, fat accumulation and energy balance centered around selected components of the TGF-² signaling system, including Activins A and B, GDF-3 and their receptors ALK7 and ALK4. Recent results from my laboratory indicate that these molecules are part of paracrine signaling networks that control important functions in pancreatic islets and adipose tissue through feedback inhibition and feed-forward regulation. These discoveries have open up a new research area with important implications for the understanding of metabolic networks and the treatment of human metabolic syndromes, such as diabetes and obesity.
To drive progress in this new research area beyond the state-of-the-art it is proposed to: i) Elucidate the molecular mechanisms by which Activins regulate Ca2+ influx and insulin secretion in pancreatic ²-cells; ii) Elucidate the molecular mechanisms underlying the effects of GDF-3 on adipocyte metabolism, turnover and fat accumulation; iii) Investigate the interplay between insulin levels and fat deposition in the development of insulin resistance using mutant mice lacking Activin B and GDF-3; iv) Investigate tissue-specific contributions of ALK7 and ALK4 signaling to metabolic control by generating and characterizing conditional mutant mice; v) Investigate the effects of specific and reversible inactivation of ALK7 and ALK4 on metabolic regulation using a novel chemical-genetic approach based on analog-sensitive alleles.
This is research of a high-gain/high-risk nature. It is posed to open unique opportunities for further exploration of complex metabolic networks. The development of drugs capable of enhancing insulin secretion, limiting fat accumulation and ameliorating diet-induced obesity by targeting components of the ALK7 signaling network will find a strong rationale in the results of the proposed work.

The aim of this proposal is to understand a novel regulatory signaling network controlling insulin secretion, fat accumulation and energy balance centered around selected components of the TGF-² signaling system, including Activins A and B, GDF-3 and their receptors ALK7 and ALK4. Recent results from my laboratory indicate that these molecules are part of paracrine signaling networks that control important functions in pancreatic islets and adipose tissue through feedback inhibition and feed-forward regulation. These discoveries have open up a new research area with important implications for the understanding of metabolic networks and the treatment of human metabolic syndromes, such as diabetes and obesity.
To drive progress in this new research area beyond the state-of-the-art it is proposed to: i) Elucidate the molecular mechanisms by which Activins regulate Ca2+ influx and insulin secretion in pancreatic ²-cells; ii) Elucidate the molecular mechanisms underlying the effects of GDF-3 on adipocyte metabolism, turnover and fat accumulation; iii) Investigate the interplay between insulin levels and fat deposition in the development of insulin resistance using mutant mice lacking Activin B and GDF-3; iv) Investigate tissue-specific contributions of ALK7 and ALK4 signaling to metabolic control by generating and characterizing conditional mutant mice; v) Investigate the effects of specific and reversible inactivation of ALK7 and ALK4 on metabolic regulation using a novel chemical-genetic approach based on analog-sensitive alleles.
This is research of a high-gain/high-risk nature. It is posed to open unique opportunities for further exploration of complex metabolic networks. The development of drugs capable of enhancing insulin secretion, limiting fat accumulation and ameliorating diet-induced obesity by targeting components of the ALK7 signaling network will find a strong rationale in the results of the proposed work.